Post by Amtram on Mar 1, 2014 13:12:02 GMT -5
From rxlist:
Mechanism Of Action
Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.
Pharmacokinetics
Pharmacokinetic studies of dextroamphetamine after oral administration of lisdexamfetamine have been conducted in patients ages 6 to 12 years with ADHD and in healthy adult volunteers.
In 18 patients ages 6 to 12 years with ADHD, the Tmax of dextroamphetamine was approximately 3.5 hours following single-dose oral administration of lisdexamfetamine dimesylate either 30 mg, 50 mg, or 70 mg after an 8-hour overnight fast. The Tmax of lisdexamfetamine was approximately 1 hour. Linear pharmacokinetics of dextroamphetamine after single-dose oral administration of lisdexamfetamine dimesylate was established over the dose range of 30 mg to 70 mg in children ages 6 to 12 years.
There is no accumulation of dextroamphetamine AUC at steady state in healthy adults and no accumulation of lisdexamfetamine after once-daily dosing for 7 consecutive days.
Food does not affect the observed AUC and Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of Vyvanse capsules but prolongs Tmax by approximately 1 hour (from 3.8 hrs at fasted state to 4.7 hrs after a high fat meal). After an 8-hour fast, the AUCs for dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.
Weight/Dose normalized AUC and Cmax were 22% and 12% lower, respectively, in adult females than in males on day 7 following a 70 mg/day dose of lisdexamfetamine dimesylate for 7 days. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients ages 6 to 12 years following single doses of 30-70 mg.
Metabolism and Excretion
After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract. Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes. Following the oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate to 6 healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces over a period of 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by 8 hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in studies of lisdexamfetamine dimesylate in volunteers.
Drug Interactions Studies
The ability of dextroamphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites, but there are no in vivo studies of p450 enzyme inhibition.
Extended release guanfacine: In a drug interaction study (N=40), administration of an extended release guanfacine (4 mg) in combination with Vyvanse (50mg) increased guanfacine maximum plasma concentration by 19%, whereas, exposure (area under the curve; AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following co-administration of extended release guanfacine and Vyvanse.
A steady-state drug interaction study with venlafaxine 225 mg and 70 mg of lisdexamfetamine resulted in a 5% decrease in d-amphetamine AUC0-tau and maximum plasma concentration values. Venlafaxine AUC0-tau and Cmax increased 13% and 10% in the study.
Lisdexamfetamine is a prodrug of dextroamphetamine. Amphetamines are non-catecholamine sympathomimetic amines with CNS stimulant activity. Amphetamines block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. The parent drug, lisdexamfetamine, does not bind to the sites responsible for the reuptake of norepinephrine and dopamine in vitro.
Pharmacokinetics
Pharmacokinetic studies of dextroamphetamine after oral administration of lisdexamfetamine have been conducted in patients ages 6 to 12 years with ADHD and in healthy adult volunteers.
In 18 patients ages 6 to 12 years with ADHD, the Tmax of dextroamphetamine was approximately 3.5 hours following single-dose oral administration of lisdexamfetamine dimesylate either 30 mg, 50 mg, or 70 mg after an 8-hour overnight fast. The Tmax of lisdexamfetamine was approximately 1 hour. Linear pharmacokinetics of dextroamphetamine after single-dose oral administration of lisdexamfetamine dimesylate was established over the dose range of 30 mg to 70 mg in children ages 6 to 12 years.
There is no accumulation of dextroamphetamine AUC at steady state in healthy adults and no accumulation of lisdexamfetamine after once-daily dosing for 7 consecutive days.
Food does not affect the observed AUC and Cmax of dextroamphetamine in healthy adults after single-dose oral administration of 70 mg of Vyvanse capsules but prolongs Tmax by approximately 1 hour (from 3.8 hrs at fasted state to 4.7 hrs after a high fat meal). After an 8-hour fast, the AUCs for dextroamphetamine following oral administration of lisdexamfetamine dimesylate in solution and as intact capsules were equivalent.
Weight/Dose normalized AUC and Cmax were 22% and 12% lower, respectively, in adult females than in males on day 7 following a 70 mg/day dose of lisdexamfetamine dimesylate for 7 days. Weight/Dose normalized AUC and Cmax values were the same in pediatric patients ages 6 to 12 years following single doses of 30-70 mg.
Metabolism and Excretion
After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract. Lisdexamfetamine is converted to dextroamphetamine and l-lysine primarily in blood due to the hydrolytic activity of red blood cells. In vitro data demonstrated that red blood cells have a high capacity for metabolism of lisdexamfetamine; substantial hydrolysis occurred even at low hematocrit levels (33% of normal). Lisdexamfetamine is not metabolized by cytochrome P450 enzymes. Following the oral administration of a 70 mg dose of radiolabeled lisdexamfetamine dimesylate to 6 healthy subjects, approximately 96% of the oral dose radioactivity was recovered in the urine and only 0.3% recovered in the feces over a period of 120 hours. Of the radioactivity recovered in the urine, 42% of the dose was related to amphetamine, 25% to hippuric acid, and 2% to intact lisdexamfetamine. Plasma concentrations of unconverted lisdexamfetamine are low and transient, generally becoming non-quantifiable by 8 hours after administration. The plasma elimination half-life of lisdexamfetamine typically averaged less than one hour in studies of lisdexamfetamine dimesylate in volunteers.
Drug Interactions Studies
The ability of dextroamphetamine and its metabolites to inhibit various P450 isozymes and other enzymes has not been adequately elucidated. In vitro experiments with human microsomes indicate minor inhibition of CYP2D6 by amphetamine and minor inhibition of CYP1A2, 2D6, and 3A4 by one or more metabolites, but there are no in vivo studies of p450 enzyme inhibition.
Extended release guanfacine: In a drug interaction study (N=40), administration of an extended release guanfacine (4 mg) in combination with Vyvanse (50mg) increased guanfacine maximum plasma concentration by 19%, whereas, exposure (area under the curve; AUC) was increased by 7%. These small changes are not expected to be clinically meaningful. In this study, no effect on d-amphetamine exposure was observed following co-administration of extended release guanfacine and Vyvanse.
A steady-state drug interaction study with venlafaxine 225 mg and 70 mg of lisdexamfetamine resulted in a 5% decrease in d-amphetamine AUC0-tau and maximum plasma concentration values. Venlafaxine AUC0-tau and Cmax increased 13% and 10% in the study.